Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice
Background and AimsDrug-induced liver injury (DILI) is a common cause of acute liver failure and represents a significant global public health problem. When discussing the gut-liver axis, although a great deal of research has focused on the role of gut microbiota in regulating the progression of DIL...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-07-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2022.944416/full |
| _version_ | 1811292597725954048 |
|---|---|
| author | Zhuoen He Zhuoen He Yunong Zeng Shuyu Li Lizhen Lin Ruisi Zhou Fangzhao Wang Wenjiao Yang Yuhao Wu Junhao Yang Ali Chen Zhang Wang Hong Yang Xiaoshan Zhao Wei Xiao Wei Xiao Lei Li Shenhai Gong Shenhai Gong |
| author_facet | Zhuoen He Zhuoen He Yunong Zeng Shuyu Li Lizhen Lin Ruisi Zhou Fangzhao Wang Wenjiao Yang Yuhao Wu Junhao Yang Ali Chen Zhang Wang Hong Yang Xiaoshan Zhao Wei Xiao Wei Xiao Lei Li Shenhai Gong Shenhai Gong |
| author_sort | Zhuoen He |
| collection | DOAJ |
| description | Background and AimsDrug-induced liver injury (DILI) is a common cause of acute liver failure and represents a significant global public health problem. When discussing the gut-liver axis, although a great deal of research has focused on the role of gut microbiota in regulating the progression of DILI, the gut commensal fungal component has not yet been functionally identified.MethodsMice were pretreated with fluconazole (FC) to deplete the gut commensal fungi and were then subject to acetaminophen (APAP) gavage. In addition, transcriptome sequencing was performed to identify differentially expressed genes (DEGs) between control and fluconazole-pretreated groups of the mice challenged with APAP.ResultsGut commensal fungi ablation through fluconazole pretreatment predisposed mice to APAP-induced hepatotoxicity, characterized by elevated serum liver enzyme levels and more severe centrilobular necrosis, which appears to be caused by robust inflammation and oxidative stress. The 16S rDNA sequencing results indicated that Akkermansia muciniphila abundance had significantly decreased in gut fungi-depleted mice, whereas increased abundance of Helicobacter rodentium was observed. The gene interaction network between DEGs identified by the transcriptome sequencing highlighted a significant enrichment of Cyp2a5 in the liver of APAP-treated mice that were preadministrated with fluconazole. Pharmacological inhibition of Cyp2a5 by 8-methoxypsoralen (8-MOP) could significantly attenuate hepatic inflammation and oxidative stress in mice, thereby conferring resistance to acute liver injury caused by APAP administration.ConclusionOur data highlighted the significance of gut commensal fungi in hepatic inflammation and oxidative stress of APAP mice, shedding light on promising therapeutic strategies targeting Cyp2a5 for DILI treatment. |
| first_indexed | 2024-04-13T04:48:38Z |
| format | Article |
| id | doaj.art-5766a386808543599d17a63cb988b622 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-04-13T04:48:38Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-5766a386808543599d17a63cb988b6222022-12-22T03:01:46ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2022-07-011310.3389/fmicb.2022.944416944416Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in MiceZhuoen He0Zhuoen He1Yunong Zeng2Shuyu Li3Lizhen Lin4Ruisi Zhou5Fangzhao Wang6Wenjiao Yang7Yuhao Wu8Junhao Yang9Ali Chen10Zhang Wang11Hong Yang12Xiaoshan Zhao13Wei Xiao14Wei Xiao15Lei Li16Shenhai Gong17Shenhai Gong18Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaDepartment of Simulation Center, Zhujiang Hospital of Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Life Science, South China Normal University, Guangzhou, ChinaSchool of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou, ChinaSchool of Life Science, South China Normal University, Guangzhou, ChinaDepartment of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaKey Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, ChinaDepartment of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaBackground and AimsDrug-induced liver injury (DILI) is a common cause of acute liver failure and represents a significant global public health problem. When discussing the gut-liver axis, although a great deal of research has focused on the role of gut microbiota in regulating the progression of DILI, the gut commensal fungal component has not yet been functionally identified.MethodsMice were pretreated with fluconazole (FC) to deplete the gut commensal fungi and were then subject to acetaminophen (APAP) gavage. In addition, transcriptome sequencing was performed to identify differentially expressed genes (DEGs) between control and fluconazole-pretreated groups of the mice challenged with APAP.ResultsGut commensal fungi ablation through fluconazole pretreatment predisposed mice to APAP-induced hepatotoxicity, characterized by elevated serum liver enzyme levels and more severe centrilobular necrosis, which appears to be caused by robust inflammation and oxidative stress. The 16S rDNA sequencing results indicated that Akkermansia muciniphila abundance had significantly decreased in gut fungi-depleted mice, whereas increased abundance of Helicobacter rodentium was observed. The gene interaction network between DEGs identified by the transcriptome sequencing highlighted a significant enrichment of Cyp2a5 in the liver of APAP-treated mice that were preadministrated with fluconazole. Pharmacological inhibition of Cyp2a5 by 8-methoxypsoralen (8-MOP) could significantly attenuate hepatic inflammation and oxidative stress in mice, thereby conferring resistance to acute liver injury caused by APAP administration.ConclusionOur data highlighted the significance of gut commensal fungi in hepatic inflammation and oxidative stress of APAP mice, shedding light on promising therapeutic strategies targeting Cyp2a5 for DILI treatment.https://www.frontiersin.org/articles/10.3389/fmicb.2022.944416/fullacetaminophengut fungiCyp2a5acute liver injuryinflammationoxidative stress |
| spellingShingle | Zhuoen He Zhuoen He Yunong Zeng Shuyu Li Lizhen Lin Ruisi Zhou Fangzhao Wang Wenjiao Yang Yuhao Wu Junhao Yang Ali Chen Zhang Wang Hong Yang Xiaoshan Zhao Wei Xiao Wei Xiao Lei Li Shenhai Gong Shenhai Gong Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice Frontiers in Microbiology acetaminophen gut fungi Cyp2a5 acute liver injury inflammation oxidative stress |
| title | Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice |
| title_full | Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice |
| title_fullStr | Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice |
| title_full_unstemmed | Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice |
| title_short | Gut Commensal Fungi Protect Against Acetaminophen-Induced Hepatotoxicity by Reducing Cyp2a5 Expression in Mice |
| title_sort | gut commensal fungi protect against acetaminophen induced hepatotoxicity by reducing cyp2a5 expression in mice |
| topic | acetaminophen gut fungi Cyp2a5 acute liver injury inflammation oxidative stress |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2022.944416/full |
| work_keys_str_mv | AT zhuoenhe gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT zhuoenhe gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT yunongzeng gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT shuyuli gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT lizhenlin gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT ruisizhou gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT fangzhaowang gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT wenjiaoyang gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT yuhaowu gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT junhaoyang gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT alichen gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT zhangwang gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT hongyang gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT xiaoshanzhao gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT weixiao gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT weixiao gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT leili gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT shenhaigong gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice AT shenhaigong gutcommensalfungiprotectagainstacetaminopheninducedhepatotoxicitybyreducingcyp2a5expressioninmice |